DIFFERENTIAL DIAGNOSIS IN RHEUMATOLOGY

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SECTION I. RHEUMATOLOGY
CHAPTER 1. OSTEOARTHRITIS
Osteoarthritis, is a term that describesa heterogeneous group of common conditions, with similar pathological and radiographic features. The most commonly affected are apophyseal joints of the cervical and lumbar spine, distal interphalangeal joints of the hand, the thumb base, the first metatarsophalangeal joint, the hips, and the knees. 
Osteoarthritis (OA) is the most common form of joint disease in humans. Our ancestors’ skeletons show that it has been with us for many centuries. However, it was only differentiated from other forms of arthritis about 100 years ago, when a combination of pathological and radiographic studies made it clear that OA is hypertrophic arthritis, in which the cartilage loss is accompanied by an increase in bone density and bone formation around the joint. 
Osteoarthritis is a strongly age-related disorder. It is uncommon before the age of 40, but its prevalence rises rapidly with age thereafter, such that most people over the age of 70 have the pathological changes of OA in some of their joints (although they may remain asymptomatic). 
Pathology and Pathogenesis 
Normal cartilage (fig. 1-1, fig. 1-2).
Normal cartilage has two main components. One is the extracellular matrix, which is rich in collagens (mainly types II, IX, and XI) and proteoglycans (mainly aggrecan). Aggrecan is a central core protein bearing numerous glycosaminoglycan chains of chondroitin sulfate and keratan sulfate, all capable of retaining molecules of water. The second component consists of isolated chondrocytes, which lie in the matrix. The matrix components are responsible for the tensile strength and resistance to mechanical loading of the articular cartilage. Chondrocytes
Elastic fibers
Хондроциты
Эластичные волокна
Fig. 1-1. Normal cartilage
Changes in articular cartilage and subchondral bone are the characteristic histopathological changes of osteoarthritis . Osteoarthritis results from a failure of chondrocytes to maintain the balance between degradation and synthesis of extracellular matrix. Increased breakdown of cartilage involves proteinases such as matrix metalloproteinase.
Fig. 1-2.Matrix components
Proinflammatory cytokines synthesized by chondrocytes and synoviocytes may drive production of cartilage-degrading enzymes. Other mediators of inflammation including prostaglandins and reactive oxygen species also contribute to OA pathogenesis (fig. 1-3).
Mechanical factors are essential for maintaining normal cartilage homeostasis and mechanical stress contributes significantly to disease initiation . 
The microcracks deepen perpendicularly in the direction of the forces of tangential cutting and along fibrils of collagen. Vertical clefts form in the subchondral bone cartilage. Clusters of chondrocytes appear around these clefts and at the surface. 
Fissures cause fragments of cartilage to detach and “fall” into the articular cavity, creating osteocartilaginous loose bodies and uncovering the subchondral bone, where microcysts develop. The loose bodies cause the mild synovial inflammation of OA. The resulting synovial inflammation often is more focal, though often just as intense, than inflammation that occurs in rheumatoid synovitis. Histologically, OA synovitis is characterized by nonspecific lymphoplasmocytic and histiocytic infiltration (fig. 1-4). 
Fig. 1-4. Nonspecific lymphoplasmocytic and histiocytic infiltration.
There is sclerosis of the subchondral bone, due to the apposition of small strips of new bone. Osteophytes form around this zone, their surface covered with fi brilar cartilage. 
Subchondral sclerosis increases with disease progression. Specific changes in the achitecture of the subchondral trabecular bone are due to accelerated bone turnover (fig. 1-5). 
Osteoarthritis is also a focal disease of joints. Unlike inflammatory arthropathies, it does not always affect the whole joint. For example, in the knee the most common parts to be affected are the medial tibiofemoral and lateral patellofemoral compartments, and the superior pole of the hip is the most likely area of that joint to be damaged. 
The main risk factor of developing of OA is present on figure 1-6.
	Fig. 1-6. Risk factor of osteoarthritis
The most frequently affected sites are the apophyseal joints of the cervical and lumbar spine, the interphalangeal joints of the hand, the thumb base, the wrist metatarsophalangeal joint, the knee and the hip. Shoulders, ankles, and metacarpophalangeal joints are amongst the less common sites of OA (fig. 1-7). 
Fig. 1-7. The most frequently affected sites of OA
	Clinical features of OA
Despite the fact that OA is described as a heterogeneous group of disorders, shared clinical features bind the group together. The two cardinal symptoms of OA are use-related pain, and relatively short-lasting stiffness or gelling of the joints after inactivity.Clinical features of OA are present in figure 1-8, 1-9, 1-10, 1-12.
· We know surprisingly little about OA pain-either
· about the patient experiences of pain or about its pathogenesis.
· Most people describe pain that is exacerbated by use of the joint, but the discomfort often continues for some time after activity ceases, wearing off slowly.
· Some people experience particularly severe but shortlasting bouts of pain on a particular movement or activity, and some experience such bouts spontaneously. In others pain can occur at night, disrupting sleep. 
· A wide variety of adjectives are used to describe the pain or discomfort. The amount of pain experienced obviously depends on what people do, and to what extent they avoid particular activities or movements that are most likely to exacerbate it, making the assessment of pain in OA problematic. 
· Similarly, gelling of joints is a somewhat mysterious symptom. The most common phenomenon seems to be difficulty initiating joint movement after inactivity, epitomized by the problems older people with OA have in “getting started” after sitting down for a while. It is not known what causes this. People may present with a variety of other symptoms, including cracking of joints (audible crepitus), joint locking, swelling, fatigue, and, of course, diffi culty with daily activities. 
· There may also be tenderness over the joint line itself. In some cases there is evidence of mild inflammation, with some warmth over the joint line and an effusion. Other common signs include weakness and wasting of the muscles acting on the joint, and areas of periarticular tenderness. In advanced cases, deformities and instability of the joints are seen. 
	Investigation
	In the majority of cases, OA can and should be diagnosed from the history and clinical signs alone, without recourse to any investigations. It is a localized disorder, without any systemic features, so blood tests are all normal with the caveat that small increases in serum C-reactive protein (CRP) can occur. 
· The main radiographic features of OA are narrowing of the joint space (due to loss of articular cartilage), osteophytes, and a variety of changes in the subchondral bone, including cysts, sclerosis, shape changes, and loss of bone volume (fig. 1-13, 1-14, 1-15).
	
	
	
Fig. 1-13.Osteoarthritis of left knee joint - narrowing of the joint space, osteophytes– III X-ray stage.
	
Fig. 1-14. Osteoarthritis of left hip joint IV X-ray stage. 
	
	
	
Fig. 1-15. Osteoarthritis of both knee joints – III X-ray stage.
	
	Diagram summarizing a hypothesis about OA x-rays and disease progression. This hypothesis, outlined in the text, considers OA to be a phasic disease process that is a response to abnormal joint biomechanics and an attempt at joint repair While the disease is active, changing joint anatomy, it con cause direct nocioceptive pain. Pain sensitization may also occur, in which case pain may persist when the disease process has ceased to be active. The plain radiograph, the most frequently used investigation in OA. will look the same whether the disease isevolving, inactive, or progressing, and whether the pain is due to direct nocioception, to periarticular problems, or results from peripheral or central pain sensitization
Fig. 1-16. X-ray investigation. 
If synovial fluid is aspirated from a joint with OA, it is generally relatively viscous and translucent in comparison with that from a patient with rheumatoid athritis, which tends to be thinner and more opaque due to the higher number of cells related to a greater degree of intra-articular inflammation. 
	Therapy
	Nonpharmacologictherapy
	An array of nonpharmacologic interventions for OAhas been described, each in various stages of development,investigation, and application. Interventions fromthis burgeoning field take advantage of gains in understanding of causes of symptoms, disease progression, function loss, and disability in persons with OA. The category of nonpharmacologic therapy in OA encompasses physical activity, exercise, weight loss, education, inserts, footwear, bracing, therapeutic ultrasound, and pulsed electromagnetic field therapy. For many of these interventions, further investigation is necessary to better define their place in OA management.
	For knee OA in particular, results from ongoing studies suggest that interventions targeting knee laxity, symptoms of knee instability, proprioceptive acuity, muscle function, agility, self-effi cacy, and specify combinations of nonpharmacologic therapies may be especially effective and should be further developed and tested. Some nonpharmacologic interventions for OA may ultimately be shown to contribute to secondary prevention, that is, prevention of disease progression. 
Table 1-1
Specific suggestions for nonpharmacologic intervention in osteoarthritis
	Adress psychosocial factors
 Enhance self-efficacy, using individualized approaches+ arthritis self-management courses 
 Educate about OA
 Improve coping skills
 Prevent/trear anxiety and depression
 Improve social support
	Improve/maintain aerobic capacity, conditioning, strength, and ADL performance
Increase physical activity
 Promote home exercise
 Refer for physical and occupational therapy
 Provide assistive devices
	Adress local factors
Adjust footwear
 Refer for insert/insoles
 Promote resistance exercise cognizant of individual pathologic anatomy 
 Refer for agility training
	Provide weight loss program for those who are overweight
Table 1-2
Recommendations (2000) for the management of knee osteoarthritis from the American college of rheumatology. 
	Nonpharmacologic therapy for patients with osteoarthritis 
Patient education
 Self-management programs 
 Personalized social support through telephone contact
 Weight loss (if overweight)
 Aerobic exercise programs
 Physical therapy
 Range-of-motion exercises
 Muscle-strengthening exercises
 Assistive devices for ambulation
 Patellar taping
 Appropriate footwear
 Lateral-wedged insoles (for genu varum)
 Bracing
 Assistive devices for activities of daily living (ADL) 
	Pharmacologic therapy for patients with osteoarthritis
 Oral 
 Acetaminophen
 COX-2-specific inhibitor
 Nonacetylated salicylate
 Other pure analgesis (tramadol, opioids)
 Intra-articular
 Glucocorticosteroids
 Hyaluronan
 Topical
 Capsaicin
 Methylsalicylate
Table 1-3
Recommendations (2003) for the management of knee osteoarthritis from a task force of the Eular standing committee for international clinical studies including therapeutics (ESCISIT) 
	The optimal management of knee OA requires a combination of nonpharmacological and pharmacological treatment modalities.
	The treatment of knee OA should be tailored according to:
 Knee risk factors (obesity, adverse mechanical factors, physical activity)
 General risk factors (age, comorbidity, polypharmacy)
 Level of pain intensity and disability
 Sign of inflammation
 Location and degree of structural damage
	Nonpharmacological treatment of knee OA should include regular education, exercise, appliances (sticks, insoles, knee bracing) and weight reducation
	Paracetamol is the oral analgesic to try first and, if successful, the preferred long-term oral analgesic
	Topical applications (NSAID, capsaicin) have clinical efficacy and are safe
	NSAIDs should be considered in patients unresponsive to paracetamol.
In patients with high gastrointestinal risk must be used selective COX-2 inhibitors 
	SYSADOA (glucosamine sulphate, chondroitin sulphate, ASU, diacerein, hyaluronic acid) have symptomatic effects and may modify structure.
	Intraarticular imjection of long-acting corticosteroid is indicated for flare of knee pain, especially if accompanied by effusion
	Joint replacement has to be considered in patients with radiographic evidence of knee OA who have refractory pain and disability
CHAPTER 2. GOUT,THE KINGS DISEASE
Gout is a clinical disease associated with hyperuricemia and caused by the deposition of monosodium urate (MSU) crystals in and around the tissues of joints. Symptomatic crystal deposition includes attacks of acute inflammatory arthritis, a chronic destructive arthropathy, and soft tissue accumulation of MSU crystals.The nonarticular (soft tissue) clinical manifestations of gout include the development of tophi and the precipitation of crystals in the renal collecting ducts, leading to urolithiasis. 
Gout is a form of inflammatory arthritis triggered by the crystallization of uric acid within the joints . Acute gout, characteristically intermittent, is one of the most painful conditions experienced by humans. Chronic tophaceous gout develops usually after years of acute intermittent gout. Beyond the morbidity associated with gout itself, the disease is associated with important medical conditions including the insulin resistance syndrome, hypertension, nephropathy.
Gout occurs predominantly among men and postmenopausal women. The disease rarely occurs in men before adolescence or in women before menopause. 
The incidence of primary gout, defined as the occurrence of this disease in the absence of a clear cause. Diet and lifestyle trends, increasing frequencies of obesity, metabolic syndrome, hypertension, organ transplantation, and increasing use of certain medications (e.g., low dose salicylate and diuretics) may explain the increasing incidence of gout.
Causes of hyperuricemia
Inherited enzyme defects:
Glucose-6-phosphatase deficiency
Hypoxanthine-guanine phosphoribosyltransferasedeficiency
Phosphoribosylpyrophosphate synthetase overactivity
Myeloproliferative or lymphoproliferative diseases
Hypertension
Diabetic ketoacidosis
Lactic acidosis
Intrinsic renal disease
Other Malignancies
Alcohol use (including lead-contaminated moonshine)
Obesity
Drugs: Diuretics
Low-dose salicylates
Pyrazinamide
Levodopa
Cytotoxic drugs
Cyclosporine
Pathogenesis
Uric acid (fig. 2-1) is a weak acid (pKa = 5.8) that exists largely as urate, the ionized form, at physiological pH. In general, the risk of upersaturation and crystal formation rises in parallel with the concentration of urate in physiologic fluids. 
	The amount of urate in the body depends on the balance between dietary intake, synthesis, and excretion of this molecule. Hyperuricemia results from the overproduction of urate (10%), underexcretion of urate (90%), or often a combination of the two. The purine precursors come from exogenous (dietary) sources or endogenous metabolism (synthesis and cell turnover). 
Urate crystals in joint fluidat the time of the acute attack may derive from rupture of preformed synovial deposits or precipitate de novo. However, the finding of crystals in synovial fluids of asymptomatic joints illustrates that factors other than the presence of crystals are important in modulating the inflammatory reaction .
Urate crystals initiate, amplify, and sustain intense inflammatory attacks by stimulating the synthesis and release of humoral and cellular mediators . Urate crystals interact with the phagocyte throughtwo broad mechanisms. First, they activate the cells through opsonized and phagocytosed particles, eliciting a stereotypical phagocyte response of lysosomal fusion, respiratory burst, and release of inflammatory mediators. 
Stages of classic gout
The course of classic gout passes through three distinct stages: asymptomatic hyperuricemia, acute intermittent gout, and advanced gout . The rate of progression from asymptomatic hyperuricemia to advanced gout varies considerably from one person to another and is dependent on numerous endogenous and exogenous factors. 
Acute Intermittent Gout
The initial episode of acute gout usually follows decades of asymptomatic hyperuricemia. Thomas Sydenham, the famous 17th-century physician who wrote of his personal experiences with gout, eloquently described the initial hours of an acute attack:
«He goes to bed and sleeps well, but about Two a Clockin the Morning, is waked by the Pain, seizing either hisgreat Toe, the Heel, the Calf of the Leg, or the Ankle;this Pain is like that of dislocated Bones, with theSense as it were of Water almost cold, poured uponthe Membranes of the part affected; presently shiveringand shaking follow with a feverish Disposition; the Pain is first gentle, but increased by degrees-till dashtowards Night it comes to its height, accompanyingitself neatly according to the Variety of the bones of theTarsus and Metatarsus, whose Ligaments it seizes,sometimes resembling a violent stretching or tearing ofthose ligaments, sometimes gnawing of a dog, andsometimes a weight; more over, the Part affected hassuch a quick and exquisite Pain, that it is not able tobear the weight of the cloths upon it, nor hard walkingin the Chamber.»
	This classic description captures the intense pain frequentlyassociated with acute gouty arthritis, and it is this clinical picture most commonly evoked by the term gout.In men, the first attacks usually occur between the fourth and sixth decades of life. In women, the age of onset is older and varies with several factors, including the age of menopause and the use of thiazide diuretics.
Typically gout arthritis – affection first metatarsophalangeal joint, atypical – other joints (fig. 2-2, 2-3). 
The onset of a gouty attack usually is heralded by the rapid development of warmth, swelling, erythema, and pain in the affected joint. Pain escalates from the faintest twinges to its most intense level over an 8- to 12-hour period. The initial attack usually is monarticular and, in one half of patients, involves the first metatarsophalangeal (MTP) joint. Involvement of the first MTP joint, which occurs eventually in 90% of individuals with gout, is known as podagra (from the Greek for “foot-trap”).
Other joints that frequently are involved in this early stage are the midfoot, ankles, heels, and knees, and less commonly, the wrists, fingers, and elbows. The intensity of pain characteristically is very severe, but may vary among subjects. As Sydenham observed, patients find walking difficult or impossible when lower extremity joints are involved. 
Systemic symptoms of acute gout
Systemic symptoms, such as fever, chills, and malaise may accompany acute gout. Fevers of higher than 38°C are seen in approximately 30% of gout patients during the early phases of acute attacks . The cutaneous erythema associated with the gouty attack may extend beyond the involved joint and resemble bacterial cellulitis. 
Acute gout varies from episodes of mild pain that resolve in several hours (“petit attacks”) to severe attacks that last 1 to 2 weeks. Early in the acute intermittent stage, episodes of acute arthritis are infrequent, and intervals between attacks last for years. Over time, the attacks typically become more frequent, longer induration, and involve more joints. 
Intercritical periods of acute intermittent gout are just as characteristic of this stage as are the acute attacks.
Previously involved joints are virtually free of symptoms.
Despite this, MSU crystals often can be identified in the synovial fluid. 
Advanced gout (sometimes referred to as chronic tophaceous gout) usually develops after 10 or more years of acute intermittent gout, although patients have been reported with tophi as their initial clinical manifestation. The transition from acute intermittent gout tochronic tophaceous gout occurs when the intercritical periods no longer are free of pain.
The subcutaneous tophus is the most characteristic lesion of advanced gout . Tophi may be found anywhere over the body, but occur most commonly in the fingers, wrists, ears, knees, olecranon bursa, and such pressure points as the ulnar aspect of the forearm and the Achilles tendon. In people with nodal osteoarthritis, tophi have a propensity for forming in Heberden’s nodes. Tophi also may occur in connective tissues at other sites, such as renal pyramids, heart valves, and sclera (fig. 2-4 – 2-13). 
Clinical Associations
Renal Disease
The only consistent visceral damage caused by hyperuricemia is its effect on the kidneys. Three forms of hyperuricemia-induced renal disease are recognized, including (1) chronic urate nephropathy, (2) acute uric acid nephropathy, and (3) uric acid nephrolithiasis. Chronic urate nephropathy is a distinct entity caused by deposition of MSU crystals in the real medulla and pyramids and is associated with mild albuminuria. 
Although chronic hyperuricemia is thought to be the cause of urate nephropathy, this form of kidney involvement is essentially never seen in the absence of gouty arthritis. Progressive renal failure is common in people with gout, but the attribution of renal failure to chronic urate nephropathy itself is often diffi cult owing to the frequent confl uence of multiple comorbid conditions in patients with gout. 
Uric acid renal stones occur in 10% to 25% of all people with gout. The incidence correlates strongly with the serum urate level, and the likelihood of developing stones reaches 50% when the serum urate is above 13 mg/dL. Symptoms of renal stones precede the development of gout in 40% of patients. 
Hypertension
Hypertension is present in 25% to 50% of people with gout, and 2% to 14% of people with hypertension have gout. Because serum urate concentration correlates directly with peripheral and renal vascular resistance, reduced renal blood flow may account for the association between hypertension and hyperuricemia. Factors such as obesity and male gender also link hypertension and hyperuricemia. 
Diagnosis
Acute onset, typically nocturnal and usually monarticular, often involving the first metatarsophalangeal joint.Postinflammatory desquamation and pruritus.Hyperuricemia in most; identification of urate crystals in joint fluid or tophi is diagnostic.Asymptomatic periods between acute attacks.Dramatic therapeutic response to NSAIDs or colchicine.With chronicity, urate deposits in subcutaneous tissue, bone, cartilage, joints, and other tissues (figure 2-14-2-16). 
Fig. 2-14. Radiographic changes of advanced gout include the typical gouty erosions with overthanging edge and soft tissue swellings of gouty tophi. 
Fig. 2-15. Gouty tophi in the II fingers of the left hands
Fig. 2-16. Radiographic changes of advanced gout include the typical gouty erosions with overthanging edge and soft tissue swellings of gouty tophi. 
Treatment
The three major considerations on comprehensive gout therapy include: (1) the treatment of acute flares; (2) management of the complications of chronic tophaceous gout; and (3) prophylaxis through urate-lowering agents designed to prevent disease flares and long-term sequelae. 
Gout management involves two primary components: (1) treatment and prophylaxis of acute joint and bursal Inflammation and (2) lowering of serum urate levels with the objectives of avoiding recurrent, painful inflammatory flares, suppressing progression of joint damage, and preventing the occurrence of urolithiasis.
All too often, current strategies for treating gouty arthritis and lowering urate levels are based more onpractitioner preferences than on evidence-based medicine. 
Management of acute gouty arthritis
	Nonsteroidal Anti-Infl ammatory 
	Drugs and Other Analgesic Agents
The primary goal in treatment of acute gout is rapid,safe resolution of pain and functional incapacity.Because acute gout attacks are self-limited, results of clinical trials for this condition warrant careful consideration. Nonsteroidal anti-infl ammatory drugs (NSAIDs) typically produce major symptom reduction within 24 hours. In the absence of contraindications, NSAIDs are considered first-line therapy for acute gout. 
No specific NSAID has clear superiority over others in the treatment of gout. Ibuprofen in full doses (e.g., 800 mg q.i.d.), for example, is as likely to be effective as indomethacin (50 mg t.i.d.). Unfortunately, NSAID gastrointestinal and renal toxicity are major concerns in many patients. 
Selective cyclooxygenase-2 (COX-2) inhibition provides an alternative approach when nonselective COX inhibitors are contraindicated in the acute setting. However, cardiac safety of selective COX-2 inhibitors remains controversial.
Glucocorticosteroids
Three days scheme :
1 day- 500 mg of methylprednisolon I/v
2 day- 250 mg of methylprednisolon I/v
3 day- 250mg of methylprednisolone I/v 
	Pharmacologic antihyperuricemicn treatments
The two major indications for chronic uric acid–lowering therapy in gout are macroscopic subcutaneoustophi and unacceptably frequent attacks of goutyarthritis (e.g., three or more per year). Standard practiceis to delay initiating uric acid–lowering treatmentuntil resolution of the inflammatory phase of acutegout. This practice is due to concern that antihyperuricemic therapy could worsen acute gout by mobilizingurate crystals from remodeling microscopic and macroscopictophi. Precipitation of acute gout through thismechanism is a common side effect in the first fewmonths after initiation of antihyperuricemic therapy.
	Allopurinol.The currently available pharmacotherapies for serum uratelowering are: allopurinol, a xanthine oxidase inhibitor, which reduces uric acid production. The usual starting dose ofallopurinol for most patients should be on the order of100 mg/day (lower for patients with renal insuffi ciency,possibly higher for young patients with normal renalfunction). This dose is titrated upward over a period ofseveral weeks according to the serum uric acid level.
Doses of up to 300 mg/day and even higher may be used. 
CHAPTER 3. RHEUMATOID ARTHRITIS:
PROBLEM FOR AGES
Rheumatoid arthritis(RA) - chronic, symmetric, erosive athritis of peripheral joints (i.e. wrists: MCP joints, and feet MTP joints) characterized by a number of extra-articular features.
Rheumatoid arthritis (RA) is one of the most common inflammatory arthritides. Affected patients suffer from chronic articular pain, disability, and excess mortality.It primarily affects the small diarthrodial joints of the hands and feet, although larger weight-bearing and appendicular joints can also be involved. Extra-articular anifestations and systemic symptoms also occur.
Risk Factors
The most potent genetic risk for RA is conveyed by certain major histocompatibility complex alleles (MHC, or HLA for human leukocyte antigen). Early studies of MHC associations relied on serologic or cellular HLA typing, which only identified a fraction of the allelic variability. Increased prevalence of RA was reported to be associated with a subset of DR4 alleles. 
Women are two to three times more likely to develop RA than men. Hormonal factors like estrogen and progesterone could potentially explain some of the gender effect. Estrogen might have detrimental effects through its ability to decrease apoptosis of B cells, potentiallypermitting the selection of autoreactive clones. Hormones also have a complex infl uence on the balance of T-cell subsets with distinct cytokine profiles. 
Several viruses have been implicated as possible etiologic factors in RA. A relationship between RA and Epstain-Barr (EBV) was suggested by several observations. For instance, EBV is a polyclonal activator of B lymphocytes and increases the production of rheumatoid factor (RF). Rheumatoid arthritis patients have an increased EBV load, and their synovium can expresses viral RNA. 
The Synovium in Rheumatoid Arthritis
The complex histological architecture of the synovial tissue in RA is the result of a dynamic process involving coordinated molecular signals (chemokines, adhesion molecules, cytokines, and growth factors) and cellular events (apoptosis, proliferation, cell migration, and survival). Increased numbers of both type A and B synoviocytes augment the depth of the lining layer, sometimes to 10 cell layers, and mononuclear cells infi ltrate the sublining (fig.3-1).
	Overgrowing of inflammated synovium- pannus formation with the cartilage an underlying bone destruction (fig. 3-2).
	The main pathogenetic mechanism of RA present in the figures 3-3 – 3-4. 
	A detailed history of the articular symptoms is ofthe utmost importance, with particular focus on themode of onset (gradual vs. acute), the pattern of jointsinvolved, and any variance in symptoms according totime of day. It is important to remember that RA isa systemic disease and individuals may thereforepresent with symptoms such as fever, weight loss, andfatigue; however, joint symptoms are usually the mostprominent.Most commonly, the onset of symptoms of joint painand swelling is insidious, occurring over weeks to months. 
	However, a minority of patients may present withan abrupt explosive onset polyarthritis. Still others maypresent with transient self-limited episodes of monoorpolyarthritis lasting days to weeks. 
Early RA:typical affection of metacarpophalangial and proximal intrafalangial joints (fig. 3-5, 3-6).As the disease progresses, larger joints such as the ankles, knees, elbows, and shoulders frequently become affected (fig. 3-7-3.9). In contrast, involvement of the temporomandibular and sternoclavicular joints and cervical spine are relatively uncommon, and the distal interphalangeal (DIP) joints and thoracolumbar spine are nearly always spared. 
Joint involvement is classically symmetrical in nature, and morning stiffness lasting more than an hour is a hallmark symptom of RA. Frequently patients with newly diagnosed RA arise from bed 1 to 2 hours earlier than usual to allow time in order to loosen up, and will often describe the need for a warm shower or for soaking their hands in warm water in order to enhance early morning function. 
Table 3-1
ACR/ EULAR criteria of Rheumatoid Arthritis 2010
	JOINT DISTRIBUTION (0-5)
	1 large joint
	0
	2-10 large joints 
	1
	1-3 small joints (large joints not counted)
	2
	4-10 small joints (large joints not counted)
	3
	>10 joints (at least one small joint)
	5
	SEROLOGY (0-3)
	Negative RF AND negative ACPA
	0
	Low positive RF OR low positive ACPA
	2
	High positive RF OR high positive ACPA
	3
	SYMPTOM DURATION (0-1) 
	<6 weeks
	0
	≥6 weeks
	1
	ACUTE PHASE REACTANTS (0-1) 
	Normal CRP AND normal ESR
	0
	Abnormal CRP OR abnormal ESR
	1
· RF- rheumatoid factor
· ACPA- anticitruline protein antibodies
· CRP- C-reactive protein
· ESR- erythrocite sedimentation rate
Table 3-2
Organ systems involved in rheumatoid arthritis
	Skin
	Rheumatoid nodules (25-50%)
	Hematologic
	Normocytlc normochromic anemia (25%-30%), thrombocytosis, thrombocytopenia," lymphadenopathy"
	Felty's syndrome
	Splenomegaly with neutropenia, large granular lymphocytes, thrombocytopenia
	Hepatic
	Nonspecific transaminitis
	Pulmonary	
	Pleural thickening, pleural effusions,
pulmonary nodules, diffuse Interstitial lung disease, ВООР, Caplan's syndrome. cricoarytenoid arthritis (pulmonary arteritis, PAH, shrinking lung)
	Cardiac
	Pericarditis, accelerated atherosclerotic disease, valvulitis
	Ophthalmologic
	Keratoconjunctlvtts sicca (10%-15%),episcleritis, sclerttls, uveitis, ulcerative keratitis
	Neurologic
	Peripheral entrapment neuropathy, cervical myelopathy due to cervical spinesubluxation
	Muscular
	Muscle atrophy. Inflammatory myositis
	Renal
	Low grade membranous glomerular nephropathy, reactive amyloid
	Vascular
	Small vessel vasculitis, systemic vasculitis
Subcutaneus rheumatoid node at the extanseble surface of elbow joint. Soft-elastic consistantion, movable, slightly painful (fig. 3-10).
Histological structure of rheumatoid node. Zone of fibrinoid necrosis surraunded by macrophages (fig.3-11).
Laboratory findings
Routine laboratory studies at baseline are important in assessing the degree of systemic infl ammation, in ruling out other potential confounding conditions, and in guiding the use of therapies that have known organspecific toxicities. These should include a comprehensivemetabolic panel, a complete blood count with differential, and inflammatory biomarkers such as the ESR and/or C-reactive protein. Approximately 25% of RA patients will have a normocytic normochromic anemia as a result of chronic inflammation.If iron deficiency anemia is found, further workup is warranted to evaluate for gastrointestinal blood loss, especially if the patient chronically uses nonsteroidal anti-inflammatory medications. 
In addition to the routine bloodwork discussed above,two autoantibodies should be assessed in patients suspected of having RA. These are the RF and anti-CCPantibodies. RFs are antibodies against the Fc portion ofIgG and can be of any immunoglobulin subclass (IgA,IgG, and IgM) but are most commonly IgM. The cutoffvalue for a positive RF varies depending on the methodology used in the local laboratory, but a common cutoff point is greater than 45 IU/mL by enzyme-linked immunoabsorbent assay (ELISA) 
Radiological findings
Radiographic abnormalities are very helpful in the diagnosisand treatment of RA. The earliest change onradiographs of the small joints of the hands and feet is periarticular osteopenia; however, this is variable, nonspecific, and nondiagnostic. More typical changes of RA are juxta-articular bony erosions and symmetrical joint space narrowing. These changes can be evident in the first 6 to 12 months of disease and accumulate over time if effective control of disease activity is not achieved. 
X-Ray Steinbrokker classification of RA (figure 3-12 – 3-15).
	
	
	Fig.3-12. Rheumatoid arthritis I X-ray stage (periarticular osteoporosis and space narrowing) 
	Fig.3-13. Rheumatoid arthritis II X-ray stage (periarticular osteoporosis, space narrowing, unique erosion)
	
	
	Fig. 3-14. Rheumatoid arthritis III X-ray stage (periarticular osteoporosis, space narrowing, Multiple cysts and erosions, subluxations in metacarpophalangial joints)
	Fig. 3-15. Rheumatoid arthritis IV X-ray stage (Multiple unkylosis)
Treatment of rheumatoid arthritis
The classes of drugs used for the treatment of RA in -clude: nonsteroidal anti-infl ammatory drugs (NSAIDs)and selective cyclooxygenase-2 (COX-2) inhibitors,DMARDs (fig. 3-16), biologics, and corticosteroids. 
Fig. 3-16. Algorithm based on the 2013 European League Against Rheumatism recommendations on RA management. ACPA, anti-citrullinated protein antibody; DMARD, disease-modifying antirheumatic drug; RF, rheumatoid factor; TNF, tumour necrosis factor.
NSAIDs andCOX-2 inhibitors are utilized primarily for symptomaticrelief of pain and are useful cotherapies because of theiranti-infl ammatory and analgesic effects. DMARDs are a diverse group of therapeutic agents that reduce the signs and symptoms of RA as well as retard radiographic progression of joint damage. This class of drugs is central to the control of RA, and is part of nearly every patient’s treatment regimen. 
Algorithm for treating active RA. In general, patients with moderate-to-severe RA are initially treated with methotrexate (MTX) therapy. Alternatively, patients with milder forms of RA may be treated initially with hydroxychloroquine (HCQ) or sulfasalazine (SSZ)and if necessary, advanced to MTX therapy depending on clinical response disease progression. 
The MTX dose may be increased from 10 to 25mg/week as tolerated, to afford optimal control of disease activity. DMARD combinations are employe for those patients with an inadequate response to MTX therapy. If patients fall to achieve any clinical benefits from MTX therapy, or are intolerant of this drug they usually switched from MTX to another DMARD such as leflunomlde or an anti-TNF blocker (not shown in the figure). If inadequateresponse to oral weekly MTX therapy, consider switching from oral to subcutaneous route of administration to improve bioavailability(EULAR, 2013). 
CHAPTER 4. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythrematosus (SLE) is a prototypic autoimmune disease with diverse clinical manifestations in association with autoantibodies to components of the cell nucleus. SLE primarily is a disease of young women, with a peak incidence between the ages of 15 and 40 and a female:male ratio of 6 to 10: 1. The age at onset, however, can range from infancy to advanced age; in both pediatric- and older-onset patients, the female:male ratio is approximately 2 : 1. 
Multiple predisposing factors have been identified. The genetic predisposition is complex, likely involving more than 100 genes. HLA-DR and DQ alleles are associated not just with the risk of developing lupus, but with the kinds of autoantibodies produced. Genes that control programmed cell death (apoptosis) are important in murine lupus models and likely in human lupus as well. 
Genes involved in immune complex clearance (Fc- receptor alleles) may predispose patients to lupus nephritis. Gene expression studies have identified an "interferon signature"—a group of genes regulated by interferon-—in the majority of SLE patients. The genetic predisposition to SLE is not overwhelming. Only 10% of patients have a first-degree relative with SLE, and SLE develops in only 2% of children who have an afflicted parent. 
Environmental factors play a role not only in the onset of SLE but also in triggering the "flares" (relapses). The most recognized environmental trigger is ultraviolet light exposure. Ultraviolet light, both ultraviolet-B and ultraviolet-A, can trigger photosensitive rashes, and more rarely, systemic flares. SLE patients are more likely than controls to have drug allergies, especially to sulfonamide antibiotics. 
Constitutional manifistations
Many SLE patients have low-grade fever (a few with temperatures higher than 39°C). Weight loss can occur, especially at presentation, but is rare. Lymphadenopathy can be found, usually small and symmetric. An acute fatigue can occur with lupus flares. Chronic fatigue is common, often as part of fibromyalgia, which occurs in as many as 30% of SLE patients.
Cutaneus syndrome present in figures 4-1 – 4-5.
Musculoskeletal manifestation
Myositis, or myopathy, is sometimes found. As many as 30% of SLE patients have coexisting fibromyalgia, which is a noninflammatory chronic pain syndrome, presenting with symmetric tender points above and below the waist. 
	Polyarthralgias and polyarthritis eventually occur in 90% of SLE patients. The arthritis is usually nonerosive, involving the small joints of the hands (proximal interphalangeal and metacarpophalangeal joints, but not distal interphalangeal joints) and wrists initially. If deformities occur, they are usually reversible ("Jaccoud arthropathy"), because they are due to tendon and ligament laxity, not to bone erosions (fig. 4-6). 
	
	
	Fig. 4-6."Jaccoud arthropathy"- absence of distructive changes
Cardiac manifestations
Cardiac manifestations include pericarditis,Libman-Sacks endocarditis with valvular vegetations, myocarditis, and coronary arteritis. Pulmonary hypertension can be primary or secondary to pulmonary emboli. Pulmonary hypertension in lupus is usually mild, but it can progress (fig. 4-7, 4-8).
	
	
	Fig. 4-7.Discoid atelectasis
	Fig. 4-8. Pleurisy, interstitial pneumonitis, both acute and chronic, discoid atelectasis may occur.
Neurologic involvement
The most common form of neurologic involvementis cognitive impairment, occurring in 80% of SLE patients 10 years after diagnosis. This likely represents permanent damage in most patients. It is more likely to progress in patients who are persistently positive for antiphospholipid antibodies. SLE can present with or include psychosis, epilepsia, encephalopathy (organic brain syndrome), coma, stroke, pseudotumor cerebri, meningitis, transverse myelitis, mononeuritis multiplex, and peripheral neuropathy. 
Seizures can represent active lupus, or represent an epileptic focus from a past stroke. Antiphospholipid antibodies increase the risk of stroke. Seizures can also be secondary to metabolic or toxic factors. Hydroxychloroquine reduces the seizure threshold, and should not be introduced unless seizures are well controlled.
Encephalopathy, formerly called organic brain syndrome, is very rare. Patients present with a change in mentation and consciousness, sometimes progressing to frank coma. The EEG will be abnormal, usually with diffuse slowing. The lumbar puncture will often show an elevated protein level, or will show an elevated IgG index or oligoclonal bands. The differential diagnosis includes metabolic or toxic factors.
Pseudotumor cerebri presents as headache. The differential diagnosis includes lupus, glucocorticoids, antiphospholipid antibodies leading to a dural sinus thrombosis, and idiopathic.
Lupus can cause meningitis, presenting as headache, often with fever and meningeal signs. The cerebrospinal fluid will be sterile, but often the protein level is increased, the white blood cell count is increased, or there are oligoclonal bands or an increased IgG index. Nonsteroidal anti-inflammatory drugs, including ibuprofen and naproxen, have rarely caused meningitis in lupus patients.
Transverse myelitis is rare in lupus. It can be seen from lupus itself, or secondary to thrombosis from antiphospholipid antibodies. Patients may first present with sensory symptoms. The physical examination will show the spinal cord level.
Mononeuritis multiplex is a vasculitis of the vaso nervorum. It presents with sensory symptoms followed by motor weakness such as foot drop, most often in the distal lower extremities. Peripheral neuropathy, including sensory neuropathies, also occur in lupus. Cranial neuropathies, such as ptosis, are rare.
Strokes can occur from active lupus. However, most strokes in SLE patients are from comorbid conditions such as hypertension, atherosclerosis, or antiphospholipid syndrome.
Haematologicsyndrome
· Anemia of chronic disease
· Neutropenia 
· Hemolytic anemia with elevated reticulocyte count
· Leukopenia 
· Thrombocytopenia
· Elevated erythrocyte sedimentation rate or C-reactive protein
· Prolonged partial thromboplastin time, or other test for lupus anticoagulant
Lupus Nephritis
Patients are usually asymptomatic, with the urinalysis or serum creatinine leading to the initial evaluation. The International Society of Nephrology has updated the previous World Health Organization classification of lupus nephritis. A renal biopsy is necessary to correctly classify the patient. Even in the lupus patient with proteinuria or hematuria, it should not be assumed that the underlying pathology is lupus nephritis. The renal biopsy may identify other lesions, including comorbidity from diabetes mellitus and hypertension, interstitial nephritis from drugs, renal vasculitis from hepatitis C (cryoglobulinemia), or microangiopathic changes (often due to antiphospholipid antibodies). Classification of lupus nephrites present on table 4-1. 
Table 4-1
Classification of lupus nephritis
	WHO classification
	Clinical manifestation
	I. Normal glomeruli
	Asymptomatic
	II. Measangial disease
	Low grade haematuira or proteinuria
	III. Focal proliferative 
glomerulonephritis 
	Nephritic urinary sediment, proteinuria
	IV. Diffuse proliferative 
glomerulonephritis
	Nephritic and nephrotic syndrome
	V.Membranous nephropathy
	Nephrotic syndrome
	VI. Sclerosing nephropathy
	Inactive urinary sediment, azotemia 
Lupus nephritis may present as proteinuria alone or proteinuria with an active urine sediment (red blood cells or red blood cell casts). Pyuria may occur as well. 
Nephrotic syndrome is common with membranous lupus nephritis. Isolated hematuria is unlikely to be due to lupus nephritis, and would prompt a search for other pathologies, such as menstrual contamination, trauma, bladder pathology such as hemorrhagic cystitis, polyp or tumor, and renal calculi.
Special Tests
Autoantibodies 
· Most (96% or more) SLE patients have a positive antinuclear antibody
· (ANA) test result. Because up to 20% of healthy young women also have a
positive ANA, the presence of an ANA alone is not given much weight. Titers of 1:640 or higher are more indicative of a connective tissue disease of some sort.
· Some autoantibodies are very specific for lupus, such as anti-dsDNA (which
occurs in about 30%) or anti-Sm (this is an abbreviation for Smith, not smooth muscle). Other autoantibodies, such as anti-Ro/SS-A, anti-La/SS-B, and anti-ribonucleoprotein, occur in SLE but also in rheumatoid arthritis and in Sjögren syndrome.
· Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-2
glycoprotein-1 are found in about 50% of SLE patients during the course of disease. They are associated with an increased risk of thrombosis and pregnancy loss. 
	
	The revised criteria for the diagnosis of systemic lupuserythematosus
	1.Malar rash
	Fixed erythema, flat or raised, over the malar eminence, tending to spare the nasolabial folds
	2. Discoid rash
	Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis
Nonerosive arthritis involving two or more peripheral joints,characterized
by tenderness, swelling or effusion
6. Serositis 
	Pleuritis; convincing history of pleuritic pain or rub heard byphysician or evidence of pleural effusionORPericarditis; documented by electrocardiogram or rub orevidence of pericardial effusion
7. Renal disorder 
	Persistent proteinuria > 500 mg per day or > 3+ if quantitation not performedOR
 Cellular casts: may be red cell, hemoglobin, granular, tubular or mixed
	8. Neurologic disorder 
	Seizures: in the absence of offending drugs or known metabolic derangement; e.g., uremia, ketoacidosis, or electrolyte imbalanceOR
Psychosis: in the absence of offending drugs or knownmetabolic derangement; e.g., uremia, ketoacidosis, or electrolyteimbalance
	9. Hematologic disorder 
	Hemolytic anemia with reticulocytosis OR 
Leukopenia: < 4000/mm3 totalOR
Lymphopenia: < 1500/mm3 on two or more occasionsOR
Thrombocytopenia: < 100,000/mm3 in the absence ofoffending drugs
10. Immunologic disorder
	Anti-DNA: antibody to native DNA in abnormal titerOR
Anti-SM: presence of antibody to SM nuclear antigenOR
Positive finding of antiphospholipid antibodies based on an abnormal serum level of IgG or IgM anticardiolipin antibodies,a positive test result for lupus anticoagulant using a standard method, or a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by treponema pallidum immobilization or fluorescent treponemal antibody absorption test
	11. ANA Abnormal titer of ANA by immunofl uorescence or equivalent assayat any point in time, in the absence of drugs known to be associatedwith drug-induced lupus syndrome 
Treatment of SLE is present in table 4-2, 4-3.
Table 4-2
Glucocorticosteroids in treatment of SLE
	Agent
	Typical Dose
	Potential Toxicities
	Follow-up
	Comments
	Glucocorticoids 
	Mild SLE: 10 mg/d
Moderate to severe SLE: 60 mg/d
	Hypertension, dys-lipidemia, atherosclerosis, hyperglycemia, osteoporosis, avas-cular necrosis, infection, weight gain, adrenal insufficiency
	Lipid profile yearly, urinalysisfor glucose, bone densitometry, blood pressure
	Regimen for organ/life-threa-teningdiseasepre-dnisone: 1 mg/kg/d or pulse I/V methylprednisolone 1 g/d x 3 d
Table 4-3
Cytostatic agents in treatment of SLE
	Hydroxychloroquine
	400 mg/d, not to exceed 6.5 mg/kg/d
	Ocular effects inclu-ding inability to focus, corneal deposits, and retinopathy; rash, hyperpigmentation, myopathy, headache
	Ophthalmologic exam with funduscopy and visual field testing yearly
	Reduce dose in renal insufficiency; ophthalmologic exam every 3 months when using chloroquine 
	Methotrexate
	7.5–15 mg/w 
	Myelosuppression, lymphoproliferative disorders, cirrhosis, pulmonary inflamma-tion and fibrosis
	Complete blood cell count (CBC), plate-lets, liver func-tion tests, albumin, crea-tinine every 8 weeks or more frequently during dose changes
	Do not use in patients with impair-ed renal function: use concomitant folic acid 1 mg/d or folinic acid 2.5 mg/wk
	Cyclophosphamide
	IV dosing: 0.5–1.0 g/mm2 monthly for 3–6 months for induction; every 3 months for maintenance
Oral dosing: Target dose of 2 mg/kg/d
	Myelosuppression, malignancy, hemor-rhagic cystitis, bladder cancer, gonadal failure, infection
	IV dosing: CBC with platelets 7–14 days after dose to determine leukocyte nadir, then every 1–3 months thereafter 
	Reduce dose in renal insufficiency, obesi-ty, and advanced age; use Pneumocy-stis carinii pneumo-nia prophylaxis; ensure adequate hydration during treatment; use antie-metics and mesna with IV dosing; con-sider use of leupro-lide in women with IV dosing
	Mycophenolate mofetil
	Target dose of 2–3 g/d
	Myelosuppression, nausea, diarrhea
	CBC and platelets every 2 weeks with dosage change, and every 8 weeks thereafter
	Reduce dose in renal insufficiency
Rituximab- monoclonal antibodies to CD-20 receptors of B-cells.
Scheme of treatment: 1000 mg i/v 2 times with 2 weeks interval, once per 6 months, Belimumab- monoclonal antibodies to B-cellular activator molecule.Scheme of treatment:10 mg per kg once per 4 weeks i/v.
CHAPTER 5. SYSTEMIC VASCULITIS
Systemic vasculities comprise a large group of inflammatory diseases with a suggestive or proven immunopathogenesis involving blood vessels of various sizes and affecting various organ systems ( ischemia and necrosis).
Primary systemic vasculitis (psv) 
Is a disorder without previously identified conditioning disease entity.
No defined preceding or accompanying disease is identified. A variety of autoantibodies are demonstrated in PSV including anti-neutrophil cytoplasmic antibody (ANCA), anti-endothelial cell antibody (EACA), circulating or localized immune complexes, and anti-DNA antibodies. 
	Secondary systemic vasculitis (ssv) 
Follows or accompanies given diseases such as infections, neoplasias or other autoimmune disorders such as connective tissue diseases.
Disease which accompanies along with ssv
· infection-associated vasculitis.
· neoplasia-associated vasculitis.
· vasculitis accompanying connective tissue diseases.
Infection-Associated Vasculitis
Leukocytoclastic vasculitis including Schoenlein-Henoch's purpura
Bacterial: streptococci, staphylococci, salmonella, yersinia, mycobateriae 
Viral: varicella-zoster, hepatitisvirus B, C, cytomegalovirus, influenza virus
Panarteritis nodosa 
Bacterial: streptococci 
Viral: hepatitisvirus A,B,C, HIV, parvovirus
Kawasaki's syndrome 
Bacterial: streptococci, samonella, yersinia, mycoplasma 
Viral: parainfluenza, rotavirus, HHV-6 
Neoplasia-Associated Vasculitis
Neoplasia Type of Vasculitis 
Non-Hodgkin's lymphoma: granulomatous, lymphocytic, leukocytoclastic,or necrotizing 
Hodgkin's disease: leukocytoclastic 
Myelogenous leukaemia: granulomatous, leukocytoclastic,or necrotizing 
Adenocarcinoma: leukocytoclastic
Carcinoma of the bronchus: leukocytoclastic
Non-Hodgkin's lymphoma: granulomatous, lymphocytic, leukocytoclastic,or necrotizing 
Myelogenous leukaemia: granulomatous, leukocytoclastic,or necrotizing 
Adenocarcinoma: leukocytoclastic
Carcinoma of the bronchus: leukocytoclastic
Vasculitis Accompanying Connective Tissue Diseases
Systemic Lupus Erythematosus (SLE)
lymphocytic proliferative vasculitis and perivasculitis with concentric
fibrosis ("onion skin")
Rheumatoid Arthritis(RA)
small vessel vasculitis with intimalproliferation, little cellular infiltrate and
immune deposits, early fibrinoid necrosis fibrosis of vessel wall 
Primary Systemic Sclerosis-Scleroderma(PSS)
proliferating (intimal) and sclerosing vasculitis 
Sjogren's syndrome(SS)small and medium sized vessels, variable: 
leukocytoclastic, mononuclear or mixed
Unclassified Connective Tissue Disease(UCTD)
Any of above 
Vasculitides can be classified by the size of the blood vessel that they 
predominantly affect (fig. 5-1).
Fig. 5-1. Classification of systemic vasculitis
Vasculitides can be classified by the size of the blood vessel that they
predominantly affect. 
	1) Large vessel vasculitis 
	 - Takayasu arteritis 
	 - giant cell arteritis 
	2) Medium vessel vasculitis 
	 - Polyarteritis nodosa 
	 - granulomatosis and polyangiitis
	 - Kawaski disease
	3) Small vessel vasculitis 
	 - Churg-straus arteritis 
	 - Microscopic polyarteritis 
 - Hypersensitivity vasculitis 
	 - Henoch-Schoenlein Purpura 
	 - Essential cryoglobulinemic vasculitis 
Classification of vasculitis entities according to supplemented chapel-hill consensus (conference 1992)
Vasculitis of Large Vessels 
· Giant cell (temporal) arteritis e.g. Horton's disease
· Takayasu's arteritis 
Takayasu Arteritis(fig. 5-2, table 5-1).
Table 5-1 
	At least 3 out of 6 criteria yields sensitivity and specificity of 90.5 and 97.8%:
· onset < 40 years 
· claudication of extremities 
· decreased pulsation of one or both brachial arteries
· at least 10 mmHg systolic difference in both arms bruit over one or both carotid arteries or abdominal aorta 
· arteriographic narrowing of aorta (fig.5-3), its primary branches, or large arteries in upper or lower extremities 
Fig. 5-3.Arteriographic narrowing of aorta
Giant cell arteritis
Chronic vasculitis of both large and medium vessels, primarily affecting cranial branches of the arteries arising from the aortic arch. 
· At least 3 out of 5 criteria yields sensitivity and specificity of 95 and 91%:
· Age at onset ≥ 50 years 
· New onset headache with localized tenderness 
· Temporal artery tenderness or decreased pulsation 
· Elevated ESR ≥ 50 mm/hour Westergren 
· Temporal artery biopsy showing vasculitis with mononuclear cell infiltrate or granulomatous inflammation, usually with multinucleated giant cells 
Polyarteritis Nodosa
Systemic necrotizing vasculitis and aneurysm formation affecting both medium and small arteries. If only small vessels are affected, it is called microscopic polyangiitis, although it is more associated with Wegener's granulomatosis than to classic PAN. 
At least 3 out of 10 criteria yields sensitivity and specificity of 82 and 87%:
· unexplained weight loss > 4 kg 
· livedoreticularis
· testicular pain 
· myalgias, weakness 
· mononeuropathy or polyneuropathy 
· new onset diastolic blood pressure > 90 mmHg 
· elevated serum creatinine (> 1.5 mg/dL) 
· hepatitis B infection 
· arterial biopsy showing polymorphonuclear cells (fig.5-4)
· arteriographic abnormalities (fig. 5-5) 
Fig. 5-5. Microaneurisms detected by angiography in polyarteritis nodosa. 
(A) Renal microaneurysms. (B) Mesenteric vessel microaneurysms 
Granulomatosis and polyangiitis
Systemic vasculitis of medium and small arteries, including venules and arterioles. Produces granulomatous inflammation of the respiratory tracts and necrotizing, pauci-immune glomerulonephritis. Most common cause of saddle nose deformity in USA (nose flattened due to destruction of nasal septum by granulomatous inflammation). Almost all patients with WG has c-ANCA, but not vice versa. Current treatment of choice is cyclophosphamide. 
At least 2 out of 4 criteria yields sensitivity and specificity of 88 and 92%.
· nasal or oral inflammation (oralulcers or purulent/bloody nasal discharge, may be painful) (fig. 5-6). 
· abnormal CXR showing nodules, infiltrates, cavities (fig. 5-7, fig. 5-8)
· microscopic hematuria or RBC casts 
· vessel biopsy shows granulomatous inflammation 
Fig. 5-7. Abnormal CXR showing nodules
	
	
	Fig. 5-8. Multifocal cavity nodules in Wegener`s granulomatosis. 
Churg-Strauss arteritis
Affects medium and small vessels with vascular and extravascular granulomatosis. Classically involves arteries of lungs and skin, but may be generalized. 
At least 4 criteria yields sensitivity and specificity of 85 and 99.7%.
· asthma (history of wheezeing or presently wheezing) 
· eosinophilia > 10% on CBC 
· mononeuropathy or polyneuropathy 
· migratory or transient pulmonary opacities on CXR 
· paranasal sinus abnormalities 
· vessel biopsy showing eosinophils in extravascular (fig. 5-9).
Table 5-2
The 1990 American college of rheumatology classification for Wegener`s granulomatosis and Churg-Strauss syndrome
	Granylematosis with Polyangiitis
	Churg-Strauss vasculitis
	Nasal or oral inflammation
	Asthma
	Painful or painless oral ulcer or bloody nasal discharge
	Wheezing or high-pitched rales 
	Abnormal chest radiograph
	Eosinophilia
	Nodules, fixed infiltrates, or cavities
	>10% of white blood cell differential
	Urinary sediment
	Mononeuropathy or polyneuropathy
	Microhematuria or red cell casts
	Mononeuropathy, multiple mononeuro-pathirs, or polyneuropathy attributable to vasculitis 
	Granulematosis inflammation on biopsy specimen
	Pulmpnary infiltrates, nonfixed
	Granulematosis inflammation within the wall of an atery or in the prevascular area
	Migratory or transitory pulmonary infiltrates 
Paranasal sinus abnormality 
Acute or chronic paranasal sinus pain, tenderness, or radiographic opcification
Extravascular eosinophilis
Biopsy of artery, arteriole, or venule showing accumulations of eosinophils in extravascular areas 
Table 5-3
Clinical features of the primary antineutrophil cytoplasmatic antibodies-associated vasculitidies
	Features
	Granulomatosis with Polyangiitis
	Microscopic Polyangiitis
	Churg-Strauss syndrome
	ANCA positivity
	80-90%
	70%
	50%
	ANCA antigen specifity
	PR3>MPO
	MPO>PR3
	MPO>PR3
	Fundamental histology
	Leukocytoclastic vasculitis; necrotizing, granulematous inflammation (rarely seen in renal biopsy specimens)
	Leukocytoclastic vasculitis; no granulematous inflammation
	Eosinophillic tissue infiltrates and vasculitis; granulomas have eosinophilic necrosis
	Ear/nose/throat
	Nasal septal perforation; saddle-nose deformity; conductive or sensorineural hearing loss, subglottic stenosis. 
	Absent or mild
	Nasal polyps; allergic rhinitis; conductive hearing loss
	Eye
	Orbital pseudotumor, scleritis (risk of scleromalacia perforans), episcleritis, uveitis
	Occasional eye disease: scleritis, episcleritis, uveitis
	Occasional eye disease: scleritis, episcleritis, uveitis
	Lung
	Nodules, infiltrates, or cavitary lesions, alveolar hemorrhage
	Alveolar hemorrhage
	Asthma, fleeting infiltrates, alveolar hemorrhage
	Kidney
	Segmental necrotizing glomerulonephritis; rare granulomatosus features
	Segmental necrotizing glomerulonephritis
	Segmental necrotizing glomerulonephritis
	Heart
	Occasional valvular lesions
	Rare
	Heart failure
	Peripheral nerve
	Vasculitis neuropathy (10%)
	Vasculitis neuropathy (58%)
	Vasculitis neuropathy (78%)
	Eosinophilia
	Mild eosinophilia occasionally
	None
	All
Henoch-Schonlein purpura
Systemic vasculitis due to tissue deposition of IgA-containing immune complexes. Biopsy of lesions shows inflammation of small vessels. It is considered a form of hypersensitivity vasculitis but is distinguished by prominent deposits of IgA. This is the most common vasculitis in children. 
Presence of 3 or more criteria yielded sensitivity of 87% while less than 2 criteria yielded hypersensitivity vasculitis in 74%:
· palpable purpura (usually of buttocks and legs) (fig. 5-9)
· bowel angina 
· GI bleed 
· hematuria 
· onset < 20 years
Behcet Disease
Diagnostic criteria of the Behcet Disease Research
Committee of Japan (1987 revision)
Major symptoms
1. Recurrent aphthous ulceration of the oral mucous membrane
2. Skin Lesions (fig. 5-10). 
· Erythema nodosum 
· Subcutaneous thrombophlebitis 
· Folliculitis, acne-like lesions 
· Cutaneous hypersensitivity 
3. Eye lesions
· Iridocyclitis 
· Chorioretinitis, retino-uveitis 
· Definite history of chorioretinitis or retino-uveitis 
4. Genital ulcers
	Antineutrophil Cytoplasmic Antibodies (ANCA)
· ANCA are antibodies directed against certain proteins in the cytoplasm of neutrophils. They are present in a high percentage of patients with systemic vasculitis, particularly Wegener's granulomatosis, as well as in patients with microscopic polyangiitis and in patients with necrotizing and crescentic glomerulonephritis. There are two major categories of ANCA based on different targets for the antibodies. 
· Cytoplasmic(c) ANCA refers to the diffuse, granular cytoplasmic staining pattern observed by immunofluorescence microscopy when serum antibodies bind to indicator neutrophils. Proteinase-3, the 29-kDa neutral serine proteinase present in neutrophil azurophilic granules is the major c-ANCA antigen. More than 90% of patients with typical Wegener's granulomatosis and active glomerulonephritis have a positive c-ANCA titer. 
· The major target for p-ANCA is the enzyme myeloperoxidase; other targets of p-ANCA include elastase, cathepsin G, lactoferrin, lysozyme, and bactericidal/permeability-increasing protein. p-ANCA have been reported to occur in variable percentages of patients with microscopic polyangiitis, polyarteritis nodosa, Churg-Strauss syndrome, crescentic glomerulonephritis, and Goodpasture's syndrome as well as in association with nonvasculitic entities such as certain rheumatic and nonrheumatic autoimmune diseases, inflammatory bowel disease, certain drugs, and infections such as endocarditis and bacterial airway infections in patients with cystic fibrosis.
Treatment: Steroids - 10-40 mg/day
Puls-therapy with steroids (3000-7000 mg for cause of treatment)
Cytotoxical drugs: 
Cyclophosphomide (200-1000 mg i/v )
Mophetil micophenolate (2000 mg/day )
Rituximab 2000 mg/2 weeks (fig. 5-16)
CHAPTER 6. SYSTEMIC SCLEROSIS
Systemic sclerosis (SSC) is a connective tissue disease of unknown etiology characterized by fibrotic changes of skin, subcutaneous tissue, viscera, abnormalities of microvasculature and immune dysfunction.
Systemic sclerosis (scleroderma) is a chronic multisystem disease that belongs to the family of systemic autoimmune disorders. The word scleroderma literally means "hard skin" and describes the most dramatic clinical feature of the disease - namely, skin fibrosis. Scleroderma affects approximately 20 new patients per million per year. As with many other autoimmune disorders, scleroderma is approximately 4-5 times more common in women than men. The average age at the time of diagnosis is approximately 50 years.
Epidemiology
SSc occurs worldwide with no racial differences. The incidence of SSc is 10/million population per year with a male to female ratio of 1:3. The peak incidence is between 30 and 50 years of age. It is rare in children.
Environmental risk factors for scleroderma-like disorders include exposure to vinyl chloride, silica dust, adulterated rape seed oil and trichlorethylene. Drugs such as bleomycin may also produce a similar picture. Familial cases have been described, but concordance in twins is rare. 
Pathology and Pathogenesis
Vascular features:
An early lesion is widespread vascular damage involving small arteries, arterioles and capillaries. There is initial endothelial cell damage with release of cytokines including endothelin-1, the latter causing vasoconstriction. There is continued intimal damage with increasing vascular permeability, leading to cellular activation, activation of adhesion molecules (E selectin, VCAM, ICAM-1), with migration of cells into the extracellular matrix. Migratinglymphocytes are IL-2 producing cells, expressing surface antigens such as CD3, CD4 and CD5. All these factors cause release of other mediators (e.g. interleukin-1,-4,-6 and -8, TGF-β and PDGF) with activation of fibroblasts. The damage to small blood vessels also produces widespread obliterative arterial lesions and subsequent chronic ischemia.
	The vascular lesion of SSc, characterized by blandintimal proliferation in the small and medium-sized arteries, results in luminal narrowing. The organs most prominently affected by obliterative vasculopathy are the heart, lungs, kidneys, and intestinal tract. Fibrosis is prominent in the skin, lungs, gastrointestinal tract, heart, tendon sheath, perifascicular tissue surroundingskeletal muscle, and in some endocrine organs(table 6-1). 
Table 6-1 
Soluble mediators of fibroblast activation elevated in systemic sclerosis
	MOLECULE
	CELLULAR SOURCE
	TGF-beta
	Inflammatory cells, platelets, fibroblasts
	PDGF
	Platelets, macrophages, fibroblasts, endothelial cells
	CTGF
	Fibroblasts
	Insulinlike growth factor 1
	Fibroblasts
	IL-4, IL-13
	Th2 lymphocytes, mast cells
	IL-6
	Macrophages, B cells, T cells, fibroblasts
	Chemokines (MCP-1, MCP-3)
	Neutrophils, epithelial cells, endothelial cells, fibroblasts
	Fibroblast growth factor 
	Fibroblasts
	Endothelin 1
	Endothelial cells
Fibrotic changes:
Fibroblasts synthesize increased quantities of collagen types I and III, as well as fibronectin and glycosaminoglycans, producing fibrosis in the lower dermis of the skin as well as the internal organs(scheme 6-1).
Scheme 6-1. Pathogenesis of systemic sclerosis.
Humoral immunity:
Humoral immunity is also involved because at least 80% of patients have antinuclear antibodies.
From a clinical point of view, scleroderma is usually divided into two main forms (schene 6-2), localized scleroderma and systemic scleroderma or systemic sclerosis . Localized scleroderma includes the disease entities ofmorphea (one or more patches of thickened skin), linear scleroderma (a line of thickened skin affecting one or more extremities), and scleroderma en coup de sabre,which is a distinct subset of linear disease that affects the forehead and face. 
Scheme 6-2. Classification of systemic sclerosis. 
Although atrophy of the subcutaneous tissue underlying the lesions typically occurs in localized scleroderma, there is usually no associated internal organ or systemic involvement.
Systemic sclerosis (SSc), on the other hand, almost always has an element of internal organ disease . SSc is divided further into limited cutaneous disease (lcSSc) and diffuse cutaneous disease (dcSSc) on the basis of the extent of skin thickening. 
The terms limited scleroderma and localized scleroderma cause linguistic confusion, but these terms refer to very different conditions.
In spite of a few reported cases of localized and systemic disease occurring in the same patient, this is a rare event and the two conditions should be thought of as two separate diseases with very different clinical pictures and prognosis. 
The obliterative small vessel vasculopathy is responsible for Raynaud’s phenomenon, scleroderma renal crisis, and pulmonary artery hypertension. In contrast, the fibrosing process results in thickened skin, pulmonary parenchymal disease, and gastrointestinal dysmotility.
Some patients have an associated infl ammatory component manifested by tendon friction rubs and synovitis. Other features such as calcinosis are less well
understood. 
Clinical features
Raynaud’s Phenomenon(fig.6-1-6-2):
It is seen in almost 85% of cases and can precede the onset of full blown disease by many years.If untreated it may lead to digital necrosis and Frank gangrene.Raynaud’s phenomenon is caused by vasospasm of the small vessels of the hands on cold exposure. This vasospasm, in turn, results in blanching, cyanosis, and then reactive hyperemia (rubor) as the affected area rewarms.
It is seen in almost 85% of cases and can precede the onset of full blown disease by many years.
An episode of Raynaud’s phenomenon canbe triggered by emotional stress, but the associationwith cold exposure must be present to make the diagnosis. Of the three phases - pallor, cyanosis, and rubor - rubor is the least frequent.
Limited cutaneous scleroderma (LcSSc)
60% of cases
Skin involvement – limited to hands, face, feet and forearms. The skin is tight over the fingers and often produce flexion deformities of the fingers. Involvement of the skin of the face produces a characteristic ‘beak-like’ nose and a small mouth (microstomia) (fig. 6-3, 6-4; 6-7, 6-9).
Painful digital ulcers and telangiectasia with dilated nail-fold capillary loops are seen. Digital ischemia may lead to gangrene (fig. 6-11).
Gastrointestinal involvement – esophageal motility dysfunction
Pulmonary hypertension develops in 10-15% of this group
Hypopigmentation of hyperpigmentation 
Swelling of puffiness of hands, fingers and feet
CREST- syndrome
· C- cacificatiotions (fig. 6-12)
Fig. 6-12. Calcifications
· R-Raynaud’s Phenomenon(fig. 6-3, 6-4)
· E- eosophagitis (fig. 6-13)
Fig. 6-13. Esophagitis. 
· S- sclerodermia(fig. 6-3, 6-7-6.9)
· T- telangiectasias (fig. 6-9)
	
	Musculoskeletal disease
Characteristics of musculoskeletal involvement includejoint contractures, tendon friction rubs, myopathy, myositis,bone resorption, cutaneous calcifi cations, synovitis,and compression neuropathies .
In the absence of infl ammatory synovitis, joint contracturesare due to involvement of overlying skin thatrestricts motion. The degree of contractures refl ects theextent of skin involvement. The hands, wrists, andelbows are the most commonly affected joints. Upperextremity involvement can interfere with normal handand arm activities. Range of motion may also be reducedat the shoulders, hips, knees, and ankles. 
Tendon friction rubs, caused by an infl ammation inthe tendon sheath, are usually palpable on examinationand sometimes cause pain with motion. If a patient complainsof pain over the tendon with joint motion and norub is palpated, it can usually be heard with the stethoscope.The most commonly affected tendon sheaths arethose of the ankle dorsiflexors, the finger extensors, andthe knee extensors. 
In SSc, both a myopathy and a myositis can occur.Scleroderma myopathy is characterized by a relativelynonprogressive course; mild proximal muscle weakness;normal or slight elevations of creatine phosphokinase(CPK); and poor response to corticosteroids .Muscle biopsy shows replacement of muscle fi bers with fibrosis, and lymphocytic infiltrates (if present) arescanty. In contrast, true myositis - a less common clinical finding -is characterized by progressive proximal muscle weakness, elevation of CPK, and typical electromyographicchanges of infl ammatory muscle disease.True myositis usually responds to immunosuppression.
Osteolysis (fig. 6-14) or bone resorption of the digital tuftsis believed to be 
on the basisof chronic ischemia.
	
	
Fig. 6-14. Osteolysis
These sites include the ribs, the mandible, the distalclavicle, the humerus and the cervical spine. Inflammatory synovitis of the peripheral joints, particularlythose of the hands and wrists, is a frequent finding early in the disease course. Joint swelling can be difficult to appreciate under the thickened and tautscleroderma skin. The arthritis of SSc is nonerosive,usually responsive to anti-infl ammatory agents (includingmethotrexate), and can resolve after several months.In contradistinction to the above situation, somepatients have an overlap of SSc and rheumatoid arthritiswith positive rheumatoid factor, erosive joint disease,and progressive articular destruction. Treatment isthe same as the treatment of idiopathic rheumatoidarthritis.
Flexion contractures andosteopenia are present (fig. 6-15). There is resorption of the distal softtissues and the distal phalangeal tufts of the thumb, index, andfifth digits. 
The most common compression neuropathy in SSc iscarpal tunnel syndrome. This frequently occurs in theedematousphase of early disease. Other compressionneuropathies, such as ulnar neuropathy, can occur asthe skin becomes thickened and taut and as fl exioncontractures develop.
Fig. 6-15.Flexion contractures. 
Lung envolvment
Pulmonary disease is now the leading cause of death in SSc. Pulmonary fi brosis occurs in many SSc patients,with 20% ultimately requiring supplemental oxygen (fig. 6-16). Patients with dcSSc are at higher risk of developing significant lung fibrosis compared to those with lcSSc.
Fig. 6-16. Interstitial fibrosis. Posteroanterior chest radiographs shows basilar linear opacities in both lungs,indicating interstitial fibrosis.
However, this distinction is not absolute, and pulmonaryfunction test (PFT) monitoring is recommended for bothgroups. Early lung disease is frequently asymptomatic.Dry cough, a later symptom, is not specifi c for lungdisease and may be related to chronic GERD. Dyspneaon exertion may be a consequence of multiple factors.Pulmonary function test that show a restrictivepattern is the most sensitive test for pulmonary parenchymaldisease. Periodic testing is suggested. Decreasesin the vital capacity, lung volumes, and/or diffusingcapacity for carbon monoxide (DLCO) are indicativeof restrictive changes. An isolated decrease in DLCOmay also indicate pulmonary hypertension.
Computed tomography (CT) scans of the lung aremore sensitive than radiographs for the detection ofearly fi brotic changes. High resolution CT views arerequired to detect a ground glass appearance, which isbelieved to represent infl ammation or alveolitis (fig. 6-17). Bronchoalveolarlavage (BAL) showing neutrophils and/oreosinophils is suggestive of active infl ammation. Patientswho are positive for antitopoisomerase antibodies areat an increased risk for clinically signifi cant pulmonary fibrosis, but this complication is not confi ned solely tothis autoantibody subgroup.
Fig. 6-17.High resolution CT detects a ground glass appearance, which represents inflammation of alveolitis and progressive fibrosing prosess in the connective tissue of the lungs.
Pulmonary hypertension can occur on the basis oftwo main pathologic processes: those primarilyinvolving destruction or obliteration of lung vasculature,such as pulmonary fi brosis, recurrent thromboembolicdisease, or scleroderma vasculopathy; or thoseassociated with decreased cardiac output, for example,diastolic dysfunction, congestive heart failure, or valvulardisease. Pulmonary arterial hypertension (PAH) is aterm used to describe the fi rst group of conditions.As noted, PFTs in patients with PAH show an isolateddecrease in DLCO with other parameters being normal,or a DLCO that is decreased out of proportion to theother measures. An echocardiogram is helpful in makingthe diagnosis, particularly if the right ventricular systolicpressure and/or the velocity of the regurgitant jet of thetricuspid valve are high. However, the echocardiogramis less reliable in borderline cases. In addition, the echocardiogramdoes not provide a measure of pulmonarycapillary wedge pressure. Right heart catheterizationshould therefore be performed in patients suspected ofPAH to confi rm the diagnosis and obtain an accuratemeasurement of both the pulmonary artery and pulmonarycapillary wedge pressures. Chronic thromboembolicdisease must be excluded in patients with PAH.In terms of symptoms, PAH is initially silent. Earlysymptoms can be nonspecifi c, for example, a sense ofgeneralized weakness on exertion. Dyspnea is a latersymptom and can be attributed to multiple other factors.PAH in SSc typically develops late in the course ofpatients with lcSSc. Many SSc patients with PAH areanticentromere antibody positive. However, in individualswith restrictive lung disease of mild or moderateseverity, it is diffi cult to distinguish which patients havePAH secondary to their lung fi brosis and which patientshave a combination of scleroderma lung disease withscleroderma pulmonary vasculopathy. The mortalityrisk in SSc patients with the combination of pulmonary fibrosis and PAH is similar to that of patients with isolatedPAH and worse than those with pulmonary fi brosisalone .
The prevalence of PAH in the SSc patient populationwhen measured by right heart catheterization is 8% to12% . The prevalence of PAH by echocardiogramalone is more than double this figure andemphasizes the point that right heart catheterization isnecessary to confi rm the diagnosis.
As echocardiography is being done more frequently inthe SSc population, it is becoming clear that this conditionis more common than believed previously, and that it canaffect both lcSSc and dcSSc patients. Risk factors for progressionto severe pulmonary hypertension include olderage, limited skin disease, and elevated pulmonary arterypressures at the time of initial evaluation.
	Cardiac involvement
If cardiac involvement in SSc is defi ned as any change in theelectrocardiogram (EKG), pericardium, or cardiacfunction, then heart disease in SSc is common.
However, clinically apparent cardiac disease, usually alate fi nding associated with a poor prognosis, is relatively uncommon. When present, SSc cardiac disease ismanifested by disturbances in the conduction system ofthe heart, arrhythmias, left ventricular or global heartfailure, and pericarditis. Patchy fi brosis throughout themyocardium is the typical histological picture in SSc.
Contraction band necrosis, characteristic of ischemia/ reperfusion injury, has been described.
Asymptomatic small or moderate-sized pericardialeffusions are frequently found, but tamponade is rare.
Large pericardial effusions, however, are associated with a poor prognosis (fig. 6-18).
	Fig. 6-18. Pericardial effusions. 
Renal disease and scleroderma renal crisis
Scleroderma renal crisis (SRC) was the most commoncause of death in SSc prior to the introduction of angiotensin-converting enzyme (ACE) inhibitors (24). SRCstill occurs, typically in the setting of early diffuse disease(<4 years from onset). In SRC, malignant hypertensioncan occur suddenly in individuals with previously normalblood pressure values. Clinical signs and symptoms arethose of severe hypertension and can include headaches,stroke, and heart failure. The creatinine is elevated andurinalysis shows proteinuria and microscopic hematuria.
Changes of microscopic angiopathy can be seenwith anemia and thrombocytopenia. Good outcomes are dependent on lowering ofthe blood pressure to truly normal levels.
Factors predictive of SRC include diffuse skin disease,rapid progression of skin involvement, disease duration<4 years, anti-RNA polymerase III antibody, newanemia, new cardiac events, and antecedent high dosecorticosteroid usage. In addition, prior use of cyclosporinehas been linked to SRC.
Poor prognostic factors in SRC include a creatininelevel >3 mg/dL at the time of diagnosis of SRC, delay inblood pressure normalization >3 days, male sex, olderage, and presence of congestive heart failure. In onestudy, 55% of patients who initially required dialysiswere able to discontinue dialysis at a mean of 8 months.It is therefore important to continue ACE inhibition andblood pressure control even after dialysis is initiated.
Normotensive renal crisis, characterized by a slowrise in creatinine in the absence of signifi cant bloodpresssure elevation and without a microangiopathicpicture, also has been described in SSc. Other causes forrenal failure must be investigated thoroughly, and ACEinhibitors employed empiricallynormalization of the blood pressure. If treated early andaggressively with ACE inhibition (combined if necessarywith other antihypertensives), the outcome isfavorable, with return to normal or near normal renalfunction within several days of blood pressure normal levels.
Gastrointestinalmanifestations
Next to skin involvement, the GI system is most commonlyaffected. Depending on the extent of involvement,signs and symptoms can include frequentheartburn, dysphagia, esophageal stricture formation,mucosal dysplasia (Barrett’s esophagus),